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Translation of abstract (English)

Apoptotic cells are generated continuously during development and tissue homeostasis of multicellular organisms. They are removed by phagocytes such as dendritic cells (DC). In contrast to pathogens, which activate DC upon uptake and lead to initiation of an immune response, apoptotic cells show an anti-inflammatory effect on DC. This protects the organism from immune reactions against self-antigens derived from apoptotic cells and, thus, from autoimmune diseases. Mechanistically, however, not much is known about the tolerogenic effect of apoptotic cells. This work shows that the protein annexin 1, which is presented specifically on the surface of early apoptotic cells, contributes to the anti-inflammatory effect by inhibiting the signal transduction of Toll-like receptors (TLR) and thus the activation of DC. The modulation of the immune response by apoptotic cells and the protein annexin 1 in particular was investigated in in vitro experiments, using DC or DC-like cell lines derived from mouse or humans. Pre-incubation with apoptotic cells or recombinant annexin 1 leads to a reduced reactivity of DC towards TLR ligands. This results in a reduced secretion of pro-inflammatory cytokines such as TNF, whereas the production of the anti-inflammatory cytokine IL-10 is unaffected. The influence on the secretion is mirrored by a corresponding regulation of the cytokine mRNAs. Gene expression analyses show a global negative impact of annexin 1 on LPS-induced proinflammatory genes. These effects are due to an inhibition of TLR-induced signal transduction. Pre-incubation with annexin 1 leads to a reduction of TLR-induced activation of MAP-kinases and NF-kB. Both pathways induced by TLR, depending on the adaptors MyD88 and TRIF, respectively, are affected: MyD88- and TRIF-dependent cytokines are inhibited to a similar extent, and the effect of annexin 1 can still be observed in MyD88-deficient mice. Correspondingly, annexin 1 inhibits activation mediated by the TRIF-dependent TLR3 as well as the MyD88-dependent signal transduction of TLR2 and the IL-1 receptor. The reactivity of the DC towards TNF, which acts via a non-TLR-related receptor, is reduced by annexin 1 as well, indicating a broad inhibition of pro-inflammatory signal transduction pathways. Experiments using the translational inhibitor cycloheximide indicated that the anti-inflammatory effect of annexin 1 depends on protein synthesis. The analysis of the effects of annexin 1 on DC contributes to a better understanding of the mechanism how apoptotic cells influence the immune system and possibly lead to peripheral tolerance.